This invention relates to compositions useful in surgery which contain a viscous or a viscoelastomeric substance or mixture of substances, such as: glycosaminoglycans, such as hyaluronic acid and salts thereof; chondroitin sulfate, alginic acid, polymannuronic acid, polyglucuronic acid and other polyglycuronic acids, mucopolysaccarides, polynucleic acids, polynucleosides, polynucleotides, polydeoxynucleic acids, polydeoxynucleosides, polydeoxynucleotides, polyamino acids, collagen and modified collagen, modified cellulose such as: methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethyleneimine, polyhydroxyethyl methacrylate and other acrylic or methacrylic acid polymers, and the like, in a physiologically compatible solution designed to minimize the traumatic effects of surgery at the cellular level. This invention also relates to methods for conducting surgery, especially ocular Surgery, which comprise administration of such compositions. The foregoing "equivalents" of hyaluronic acid are not publicly known, and constitute distinct embodiments of the present invention.
Hyaluronic acid, a preferred and representative viscoelastic substance for the compositions of the present invention, is a naturally occurring high viscosity glycosaminoglycan having alternating .beta. 1-3 glucuronidic and .beta. 1-4 glucosaminidic bonds. The molecular weight of this material is generally within the range of 50,000 to 8,000,000, although there are reports of molecular weights as high as 13,000,000 depending on the source, method of isolation and method of determination. It is found in animal tissue, e.g., umbilical cord, skin, vitreous humour, synovial fluid, rooster combs, and can be obtained from fermentation via Groups A and C hemolytic streptococci.
The isolation and characterization of hyaluronic acid is described in Meyer, et al., J. Biol. Chem. 107, 629 (1934); J. Biol. Chem. 114, 6589 (1936); Balase, Fed. Proc. 17, 1086 (1958); and Laurent, et al., Biochem. Biophys. Acta 42. 476 (1960). The structure of hyaluronic acid was elucidated by Weissman, et al., J. Am. Chem. Soc. 76, 1753 (1954), and Meyer, Fed. Proc. 17, 1075 (1958).
Hyaluronic acid and its aforementioned equivalents are useful therapeutic injection materials because of their noninflammatory response and physical properties of being viscous and viscoelastic. Hyaluronic acid is a natural component of the humours of the eye. Thus, hyaluronic acid approaches the ideal implant material when conducting eye surgery, which involves displacement or removal of vitreous and aqueous humours. The above listed natural, semisynthetic, and synthetic equivalents of hyaluronic acid behave similarly. Such materials are readily available.
U.S. Pat. No. 4,141,973 to Balazs describes an ultrapure hyaluronic acid composition for use in ocular surgery. This composition is essentially a 1.0 weight percent solution of the sodium salt of hyaluronic acid dissolved in an aqueous physiological buffer. There is also available commercially, under the trademark "HEALON;" a physiologically buffered 1.0 weight percent solution of sodium hyaluronate. Literature which discusses this product states that the product does not increase intraocular pressure postoperatively in humans and that it has been used in anterior segment eye surgery, Miller, et al., American Intraocular Implant Society Journal, Vol. 6, No. 1, pp. 13-15 (1980). This product is also discussed, for example, in U.S. Pat. No. 4,328,803; wherein it is also stated that the intracameral dilution of "HEALON" with balanced salt solution at the end of the ophthalmic surgical procedure eliminated postoperative pressure elevation.
Hyaluronic acid or the commercially available sodium hyaluronate product have been reported in various publications. Thus, in a publication by Balazs, et al., Mod. Prob. of Ophthal., Vol. 10, pp. 3-21, 1972, the authors discuss hyaluronic acid and replacement of vitreous and aqueous humours, including the observation that the kinematic viscosity of hyaluronic acid jelly dissolved in physiologically balanced salt solution may be used. In an article by Hultsch, Ophthalmology 87(7), p. 706, 1980, there is a discussion of the scope of hyaluronic acid as an experimental intraocular implant. In a publication by Pape, et al., Ophthalmology 87(7), p. 699, 1980, there is a report of the use of sodium hyaluronate in human anterior segment surgery in a wide spectrum of procedures. The authors conclude that the product is safe and facilitates the outcome of surgery, and also results in significantly decreased endothelial cell loss. The authors reported that the product is a viscoelastic jelly manufactured by Pharmacia Company, Inc. It is said to have a viscosity of over 400,000 times that of a balanced salt solution.
A substantial amount of additional work has been done to evaluate the effects of sodium hyaluronate in ocular surgery. This work has been reported, for example, in ARVO Abstracts (1983, 1984) by Meyer, et al., and by McCulley, et al. These abstracts are concerned with the in vitro evaluation of the corneal endothelium after exposure to hyaluronate as well as the tolerance limits therefor.
While substantial work has been done relative to the use of hyaluronic acid (primarily as the sodium salt which is sold commercially for eye surgery), there remains a need in the art for hyaluronic acid and other viscoelastic compositions and methods of administration of such compositions which provide even greater improvements in the compatibility of such viscous and viscoelastic implants. The present invention meets this need.
It is accordingly an object of the invention to provide novel compositions of matter for use in surgery, especially ocular surgery.
A further object of the invention is to provide compositions comprising a viscous or a viscoelastic material, such as hyaluronic acid or an alkali metal salt thereof, in a physiologically compatible solution, and to provide methods for the administration of such compositions during surgery, especially ocular surgery.
In satisfaction of the foregoing objects, this invention provides a composition of matter useful in surgical manipulations and as an implant material which comprises a solution of hyaluronic acid or an alkali metal salt thereof, or a functional equivalent thereof, such as those viscous and viscoelastic materials representively listed above, and a physiologically compatible salt solution; said salt solution having a pH of between 6.8 and 8.0 and an osmolality of between 250 and about 350 mOsm/kg and comprising sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate ions, dextrose and glutathione or the equivalent amount of reduced glutathione, or other suitable sulfhydryl containing compound either in its reduced or oxidized form.
The present invention also provides a method for conducting surgery, e.g., ocular surgery, which comprises implantation or administration of the compositions of the present invention for mechanical purposes or for functional replacement of withdrawn humour, wherein the physiologically compatible salt solution vehicle provides the necessary environment to minimize the traumatic effects of surgery at the cellular level by maintaining, inter alia, the function of intracellular respiratory enzymes .